CENTER FOR DRUG EVALUATION AND RESEARCH...Supervisor: Sushanta Chakder, PhD Division Director: Donna...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

208399Orig1s000

NON-CLINICAL REVIEW(S)

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DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AND RESEARCH

PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION

Application number: 208399

Supporting document/s: 042

Applicant’s letter date: 4/25/2017

CDER stamp date: 4/25/2017

Product: Varubi® (rolapitant) (Injectable Emulsion for Intravenous Use)

Indication: Prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy

Applicant: Tesaro, Inc.

Review Division: Division of Gastroenterology and Inborn Errors Products (DGIEP)

Reviewer: Tamal Chakraborti, PhD

Supervisor: Sushanta Chakder, PhD

Division Director: Donna Griebel, MD

Project Manager: Mary Chung, PharmD

Reference ID: 4152496

NDA # 208399 Reviewer: Tamal Chakraborti, PhD

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TABLE OF CONTENTS

EXECUTIVE SUMMARY..................................................................................................3INTRODUCTION ................................................................................................................3BRIEF DISCUSSION OF NONCLINICAL FINDINGS ..................................................................3RECOMMENDATIONS ........................................................................................................3DATA ..............................................................................................................................6REGULATORY BACKGROUND ............................................................................................8

STUDIES SUBMITTED ....................................................................................................8STUDIES REVIEWED.........................................................................................................8STUDIES NOT REVIEWED .................................................................................................8PREVIOUS REVIEWS REFERENCED ...................................................................................8

INTEGRATED SUMMARY AND SAFETY EVALUATION ..............................................8APPENDIX/ATTACHMENTS...........................................................................................9



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Executive SummaryIntroductionRolapitant is a substance P/Neurokinin 1 (NK1) receptor antagonist. An oral version (Varubi® tablets) of rolapitant was approved on September 01, 2015. This application is for an intravenous (IV) version [Varubi® IV (rolapitant) injectable emulsion, for intravenous use] of rolapitant. Varubi injectable emulsion is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The recommended dosage is 166.5 mg administered as an IV infusion over 30 minutes within 2 hours prior to the initiation of chemotherapy on Day 1.

The original NDA was submitted on March 11, 2016. This resubmission is a complete response to the deficiencies outlined in the Division’s Complete Response (CR) letter dated January 11, 2017.

Brief Discussion of Nonclinical FindingsThe Applicant did not submit any nonclinical study report in this submission. Nonclinical studies have been conducted with rolapitant to support approval of rolapitant tablets and rolapitant injectable emulsion under NDA 206500 and NDA 208399, respectively. Please refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD and pharmacology review of NDA 208399 dated November 28, 2016 by Tamal Chakraborti, PhD.

RecommendationsApprovabilityThere are no nonclinical approvability issues.Additional Non Clinical RecommendationsNone

LabelingNonclinical sections of the proposed draft labeling of VARUBI® conforms to the content and format of labeling for human prescription drug and biological products under 21CFR201.57. However, the following revisions are recommended.

8.1 Pregnancy

Applicant’s Version:



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Evaluation: The Applicant’s proposed version appears to be acceptable. However, the following revisions (rolapitant hydrochloride to rolapitant) are made.

Recommended Version:

8.2 Lactation

Data

Radioactivity from labeled [14C] rolapitant was transferred into milk of lactating rats following a single oral dose of 22.5 mg/kg, and the maximum radioactivity in milk was observed at 12 hours post-dose. The mean milk/plasma radioactivity concentration ratios in dams at 1 to 48 hours post-dose ranged from 1.24 to 3.25. Based on average daily consumption of milk (2 mL/day) and the maximum milk radioactivity determined, pup exposure is expected to be 0.32% of the orally administered dose.

8.4 Pediatric Use

Applicant’s Version:

Evaluation: The results of the oral juvenile animal toxicology study in rats are incorporated.

Recommended Version:

8.4 Pediatric Use

Juvenile Animal Toxicity Data

In an oral juvenile toxicity study in rats rolapitant dose of 11.3, 22.5 and 45 mg/kg/day from postnatal Day 7 through PND 70 (equivalent human age of newborn to 16 years), a delay in the attainment of balanopreputial separation in males and acceleration of the attainment of vaginal patency in females at 22.5 and 45 mg/kg/day (approximately 1.3 and 2.6 times, respectively, the recommended intravenous human dose on a body surface area basis). Treated males and females were mated following a 2-week wash-out period after the last dose.(approximately 1.3 and 2.6 times, respectively, the recommended intravenous human dose on a body surface area basis). There were lower mean numbers of implantation sites, corpora lutea, and mean number of viable embryos at these doses when compared to control.


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MutagenesisRolapitant was not genotoxic in an Ames test, a human peripheral blood lymphocyte chromosome aberration test, and a mouse micronucleus test.

Impairment of FertilityIn a fertility and early embryonic development study in female rats, rolapitant at an oral dose of 9 mg/kg per day (approximately 0.5 times the recommended intravenous human dose on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a rolapitant dose of 4.5 mg/kg per day (approximately 0.3 times the recommended intravenous human dose on a body surface area basis), there were slight decreases in the number of corpora lutea and implantation sites. Rolapitant did not affect the fertility or general reproductive performance of male rats at doses up to 90 mg/kg per day (approximately 5.2 times the recommended intravenous human dose on a body surface area basis).

Regulatory Background Original NDA was submitted on March 11, 2016 Complete Response (CR) letter was issued on January 11, 2017 End of review meeting was held on March 22, 2017 to discuss the Applicant’s

plan to address the deficiencies identified in the above CR letter.

Studies SubmittedStudies Reviewed The Applicant did not submit any nonclinical study report in this submission.

Studies Not Reviewed N/A

Previous Reviews Referenced Pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L.

Behrsing, PhD Pharmacology review of NDA 208399 dated November 28, 2016 by Tamal

Chakraborti, PhD Pharmacology review of IND 72,754 dated December 20, 2016 by Tamal

Chakraborti, PhD Pharmacology review of IND 72,754 dated August 23, 2017 by Tamal

Chakraborti, PhD

Integrated Summary and Safety EvaluationThe Applicant did not submit any nonclinical study report in this submission. Nonclinical studies have been conducted with rolapitant to support approval of rolapitant tablets and



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rolapitant injectable emulsion under NDA 206500 and NDA 208399, respectively. A Complete Response letter was issued on January 11, 2017. However, no nonclinical safety issues were identified in the initial submission. In the current review, some labeling changes are recommended. In addition, a recommendation to add the findings of the oral juvenile rat toxicity study was also made in Section 8.4 of the label.

Appendix/AttachmentsNone


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

TAMAL K CHAKRABORTI09/14/2017

SUSHANTA K CHAKDER09/14/2017


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DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AND RESEARCH

PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION

Application number: 208399

Supporting document/s: 001

Applicant’s letter date: 3/11/2016

CDER stamp date: 3/11/2016

Product: Rolapitant hydrochloride (Varubi®, Injectable Emulsion for Intravenous Use)

Indication: Prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy

Applicant: Tesaro, Inc.

Review Division: Division of Gastroenterology and Inborn Errors Products (DGIEP)

Reviewer: Tamal Chakraborti, PhD

Supervisor: Sushanta Chakder, PhD

Division Director: Donna Griebel, MD

Project Manager: Mary Chung, PharmD

Disclaimer

Except as specifically identified, all data and information discussed below and necessary for approval of NDA 208399 are owned by Tesaro, Inc. or are data for which Tesaro, Inc. has obtained a written right of reference. Any information or data necessary for approval of NDA 208399 that Tesaro, Inc. does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 208399.



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TABLE OF CONTENTS

1 EXECUTIVE SUMMARY...........................................................................................41.1 INTRODUCTION .....................................................................................................41.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................41.3 RECOMMENDATIONS .............................................................................................4

2 DRUG INFORMATION..............................................................................................82.1 DRUG ..................................................................................................................82.2 RELEVANT INDS, NDAS, AND DMFS .....................................................................92.3 DRUG FORMULATION ............................................................................................92.4 COMMENTS ON NOVEL EXCIPIENTS ......................................................................102.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ........................................122.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .....................................212.7 REGULATORY BACKGROUND ...............................................................................22

3 STUDIES SUBMITTED...........................................................................................223.1 STUDIES REVIEWED ............................................................................................223.2 STUDIES NOT REVIEWED.....................................................................................223.3 PREVIOUS REVIEWS REFERENCED.......................................................................23

4 PHARMACOLOGY .................................................................................................234.1 PRIMARY PHARMACOLOGY ..................................................................................234.2 SECONDARY PHARMACOLOGY .............................................................................234.3 SAFETY PHARMACOLOGY ....................................................................................23

5 PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................245.1 PK/ADME .........................................................................................................245.2 TOXICOKINETICS .................................................................................................24

6 GENERAL TOXICOLOGY......................................................................................246.1 SINGLE-DOSE TOXICITY ......................................................................................246.2 REPEAT-DOSE TOXICITY .....................................................................................24

7 GENETIC TOXICOLOGY........................................................................................657.1 IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) .......................657.2 IN VITRO ASSAYS IN MAMMALIAN CELLS ...............................................................657.3 IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY) ..................657.4 OTHER GENETIC TOXICITY STUDIES.....................................................................65

8 CARCINOGENICITY...............................................................................................669 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................66

9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT................................................669.2 EMBRYONIC FETAL DEVELOPMENT.......................................................................669.3 PRENATAL AND POSTNATAL DEVELOPMENT ..........................................................66



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10 SPECIAL TOXICOLOGY STUDIES....................................................................6611 INTEGRATED SUMMARY AND SAFETY EVALUATION..................................6612 APPENDIX/ATTACHMENTS ..............................................................................67



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1 Executive Summary1.1 IntroductionRolapitant is a substance P/Neurokinin 1 (NK1) receptor antagonist. An oral version (tablets, Varubi®) of rolapitant was approved on September 01, 2015. This application is for an intravenous (IV) version [Varubi® IV (rolapitant) injectable emulsion, for intravenous use] of rolapitant. Varubi injectable emulsion is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The recommended dosage is 166.5 mg administered as an IV infusion over 30 minutes within 2 hours prior to the initiation of chemotherapy on Day 1.

1.2 Brief Discussion of Nonclinical FindingsNonclinical studies have been conducted with rolapitant to support approval of rolapitant tablets under NDA 206500. Please refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

Toxicology studies in two species (rat and cynomolgus monkey) were conducted up to 13 weeks treatment duration by the IV route to support the IV rolapitant formulation. The Central Nervous System (CNS) appeared to be the primary target organ in both species. Treatment related clinical signs included convulsions and tremors, which were consistent with the findings of the oral toxicology studies. However, there were no rolapitant related histopathological findings in the brain in the above IV toxicology studies in both species. Vehicle related effects (clinical pathology changes and histopathology changes in the adrenal gland and liver) were observed in the IV toxicology studies. Histopathological findings in the adrenal gland (diffuse vacuolation of the adrenal cortex and brown pigmentation of adrenal glands) and liver (Kupffer cells) appeared to be related to the vehicle. In addition, infusion site reactions were observed, which included abscess formation and/or inflammation.

1.3 Recommendations1.3.1 ApprovabilityThere are no nonclinical approvability issues.1.3.2 Additional Non Clinical RecommendationsNone1.3.3 LabelingNonclinical sections of the proposed draft labeling of VARUBI® conforms to the content and format of labeling for human prescription drug and biological products under 21CFR201.57. However, the following revisions are recommended.



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Rolapitant hydrochloride was not genotoxic in an Ames test, a human peripheral blood lymphocyte chromosome aberration test, and a mouse micronucleus test.

In a fertility and early embryonic development study in female rats, rolapitant at an oral dose of 9 mg/kg per day (approximately 0.5 times the recommended intravenous human dose of 166.5 mg on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a dose of 4.5 mg/kg per day (approximately 0.2 times the recommended intravenous human dose of 166.5 mg on a body surface area basis), there were slight decreases in the number of corpora lutea and implantation sites. Rolapitant did not affect the fertility or general reproductive performance of male rats at doses up to 90 mg/kg per day (approximately 5.2 times the recommended intravenous human dose of 166.5 mg on a body surface area basis).

2 Drug Information2.1 Drug

CAS Registry Number:

Rolapitant (USAN rolapitant): 552292-08-7 Rolapitant hydrochloride (USAN rolapitant hydrochloride): 914462-92-3

Generic Name: Rolapitant hydrochloride

Code Name: SCH 619734 hydrochloride or 17TR68M Rolapitant

Chemical Name: (5S,8S)-8-[[(1R)-1-[3,5 Bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride

Molecular Formula/Molecular Weight:

Rolapitant (USAN rolapitant): C25H26F6N2O2/500.49 Rolapitant hydrochloride (USAN rolapitant hydrochloride): C25H29ClF6N2O3 or C25H26F6N2O2.HCl.H2O/554.96

Structure: The following figure (from page 1 of Section 3.2.S.1 of the submission) shows the structure of rolapitant hydrochloride.


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Pharmacologic Class: Substance P/Neurokinin 1 (NK1) receptor antagonist

2.2 Relevant INDs, NDAs, and DMFs IND 72754 (Rolapitant Oral, Tesaro, Inc.) IND 117307 (Rolapitant, IV, Tesaro, Inc.) NDA 206500 (Rolapitant, Oral, Tesaro, Inc.)

2.3 Drug FormulationRolapitant (Varubi) injectable emulsion for IV infusion is a sterile formulation containing 166.5 mg rolapitant (equivalent to 185 mg of rolapitant hydrochloride) and the following inactive ingredients: polyoxyl 15 hydroxystearate (44 mg/mL), medium chain triglycerides (11 mg/mL), soybean oil (6. mg/mL), sodium chloride (6.2 mg/mL) dibasic sodium phosphate, anhydrous (2.8 mg/mL), and may contain hydrochloric acid and/or sodium hydroxide to adjust pH. Varubi injectable emulsion is supplied as a sterile, translucent white homogenous emulsion in a stoppered vial. Each vial delivers 166.5 mg/92.5 mL (1.8 mg/mL) rolapitant. The following table (from page 1 of Section 2.3.P of the submission) shows the composition of the drug product (DP).


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2.7 Regulatory Background Type B meeting was held on April 5, 2010 to discuss the phase 3 development

program. Type C End of Phase (EOP) 2 follow-up meeting was held on July 5, 2011 to

discuss revised clinical development program. Type B EOP2 meeting was held on January 28, 2013 to discuss the Chemistry,

Manufacturing, and Controls (CMC) strategy of rolapitant. Type B Pre-NDA meeting was held on July 2, 2014. Type B Pre-NDA meeting was held on July 2, 2014. Type B Pre-NDA meeting to discuss the clinical and nonclinical content for the

planned NDA for rolapitant injection.

3 Studies Submitted3.1 Studies Reviewed The Applicant has submitted all study reports, which were also submitted under NDA 206500 for rolapitant oral tablet. Please refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

The following study reports are reviewed here.

STUDY TITLE REPORT NO./Submission No. PAGEPHARMACOKINETICS 24Protein Binding Study for SCH 720881 DM27583 24TOXICOLOGY 24Repeat-Dose 24Rat 247-Day, Intravenous, Dose Range Finding (DRF) 14-3882 3414-Day, Intravenous, DRF 14-3875 346-Week, Intravenous -276501/SDN 016 2413-Week, Intravenous 15-3889 3213-Week, Intravenous 15-3893 33Monkey 4528-Day, Intravenous 2013-012 4513-Week, Intravenous 2013-015 54

3.2 Studies Not Reviewed The following study reports were not reviewed.


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3.3 Previous Reviews Referenced Pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L.

Behrsing, PhD Pharmacology review of IND 117,307 dated August 14, 2013 by Tamal

Chakraborti, PhD Pharmacology review of IND 72754 dated July 2, 2015 by Tracy L. Behrsing,

PhD Pharmacology review of IND 72,754 dated May 9, 2012 by Tamal Chakraborti,

PhD Pharmacology review of IND 72,754 dated December 5, 2012 by Tamal

Chakraborti, PhD Pharmacology review of IND 72,754 dated November 24, 2010 by Tamal

Chakraborti, PhD Pharmacology review of IND 72,754 dated March 10, 2006 by Ke Zhang, PhD Pharmacology review of IND 72,754 dated December 29, 2005 by Ke Zhang,

PhD

4 Pharmacology4.1 Primary PharmacologyPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

4.2 Secondary PharmacologyPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

4.3 Safety PharmacologyPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.


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5 Pharmacokinetics/ADME/Toxicokinetics5.1 PK/ADME

5.2 Toxicokinetics

Protein Binding Study for SCH 720881 (DM27583)

Methods: In this study, the stability of 3H-SCH 720881 (metabolite of rolapitant) in the plasma and ultrafiltrate (UF) from the mouse, rat, rabbit, dog, monkey, and human was evaluated using High Pressure Liquid Chromatography (HPLC). Specific binding of 3H-SCH 720881 to human plasma proteins was measured as a function of time. 3H-SCH 720881 was incubated at a concentration of 0.2 μg/mL at 370C for up to 30 hours.

Results: Under the conditions of the study, 3H-SCH 720881 was stable in the plasma and UF from all six species up to 30 hours at 370C. In the human plasma, protein binding ranged from 99.5-100%. Data for other species was not provided in the report.

6 General Toxicology6.1 Single-Dose ToxicityPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

6.2 Repeat-Dose Toxicity

Study title: 6-Week Intravenous Infusion Toxicity and Toxicokinetic Study in Sprague Dawley Rats with a 6-Week Recovery Period

Study no.: -276501Study report location: EDR SDN 016, Section 4.2.3.2

Conducting laboratory and location: Date of study initiation: October 5, 2015

GLP compliance: YesQA statement: Yes

Drug, lot #, and % purity: Rolapitant, Lot no. 22903.003, 101%

Key Study Findings: There two deaths in males (vehicle control and 20 mg/kg) and two deaths in

females (vehicle control and 20 mg/kg). These deaths were not considered treatment related.

There were no significant treatment related clinical signs or effects on body weight.

In males, higher Alkaline Phosphatase (ALP) and Alanine Aminotransferase (ALT) levels were observed at 20 mg/kg. Relation to the treatment was unknown


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in the absence of dose response (as only one dose group was tested in this study), lack of histopathological correlates and values (ALP) were within the historical control range.

There were no significant treatment related gross necropsy findings Histopathological changes were observed in the lung (subacute inflammation,

edema, and hemorrhage), infusion site (intimal thickening, intravascular thrombosis, medial hypertrophy, subacute inflammation of the vessel walls, and perivascular hemorrhage), testes (hypospermatogenesis in one of the testes and unilateral hypospermia in the epididymis), and liver (mild periportal vacuolation of hepatocytes in one male at 20 mg/kg, another 20 mg/kg/dose group male had a locally extensive chronic infarct of a liver lobe characterized by hemorrhage and fibrosis with little remaining hepatic parenchyma). The relation to the treatment was unknown in the absence of dose response (only one dose was tested in this study) and these were also observed in control animals.

The NOAEL could not be determined as only one dose was tested in this study.

Methods: In a 90-day intravenous (IV) study in rats (Study No. 15-3893), daily IV administration via femoral cannulas resulted in a vehicle related increase in infection. The current study was designed to test the hypothesis that a less frequent dosing regimen would reduce and/or eliminate infection.

Doses: 0 (saline), 0 (vehicle), 20 mg/kgFrequency of dosing: Once biweekly (4 total doses; Days 0, 14, 28,

and 42)Route of administration: IV infusion (30-minute)

Dose volume: 10 mL/kgFormulation/Vehicle: 4.4% Solutol® HS15, 1.1% Medium-Chain

Triglycerides (MCT), and 0.66% soybean oil in 20 mM Phosphate-Buffered Saline (PBS) pH 7.5.

Species/Strain: Sprague Dawley (SD) ratsNumber/Sex/Group: 10-25/sex/group

Age: Males and females were 10-12 weeks old. Weight: All males and females weighed more than 220 g

at the initiation of the treatment.Satellite groups: Toxicokinetic (TK)

Unique study design: Shown in the table below Deviation from study protocol: Protocol deviations did not negatively impact the

quality or integrity of the data or the outcome of the study results.

The study design is shown below (from page 32 of the report).



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Basis of Dose Selection: The 20 mg/kg dose was considered as the highest tolerated dose in a 90-day IV study in rats (Study No. 15-3893). As stated above, in the above 90-day study, daily IV administration via femoral cannulas resulted in a vehicle-related increase in infection. This study was designed to test the hypothesis that a less frequent dosing regimen would reduce and/or elimination infection.

Observations and Results:

Mortality: All animals were observed twice daily for mortality and moribundity.

There were no deaths attributed to administration of the test article or vehicle (placebo). There were 2 early deaths in males (one animal in the vehicle control group and one animal at 20 mg/kg). Animal number 8287 (20 mg/kg, male) was euthanized due to an exposed catheter on Day 8. Microscopic findings for this animal included unorganized intravascular thrombus in the right ventricle and mild hemorrhage in the lung. The reason for euthanasia was unrelated to test article administration. Animal no. 8206 (vehicle control, male) was found dead on Day 14. The cause of death was undetermined. The animal had a small intravascular unorganized thrombus in the right ventricle and medial hypertrophy of vessel walls in the lungs. The changes in the lungs in both males were considered related to, and consequences of, IV infusion.

There were 2 early deaths in females. Animal no. 8365 (vehicle control, female) was found dead on Day 15 with an undetermined cause of death. There was mild subacute



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inflammation of the lung, but this finding was not of a severity to be the cause of death. Animal no. 8348 (20 mg/kg, female) was assigned as a recovery animal, and was euthanized due to an exposed port on Day 78. The animal had minimal subacute inflammation of the lung, a well-delineated focus of necrotizing inflammation at the infusion site, and decreased numbers of corpora lutea in the ovary (consistent with senescence). The reason for euthanasia was unrelated to test article administration.

Clinical Signs: Clinical signs were observed prior to infusion and at approximately 45 minutes following the end of infusion. There were no significant treatment related clinical signs.

Body Weights: Body weights were recorded on a weekly basis.

The mean initial (Week 0) and final (Week 6) body weights of saline control males were 321 and 490 g, respectively. The mean initial (Week 0) and final (Week 6) body weights of vehicle control males were 325 and 500 g, respectively. The mean initial (Week 0) and final (Week 6) body weights of saline control females were 265 and 490 g, respectively. The mean initial (Week 0) and final (Week 6) body weights of vehicle control females were 324 and 332 g, respectively. There were no significant treatment related effects on body weight.

Feed Consumption: Food consumptions were recorded on a weekly basis.

The mean initial (Week 0-1) and final (Week 5-6) food consumption of saline control males were 27 and 22 g/animal/day, respectively. The mean initial (Week 0-1) and final (Week 5-6) food consumption of vehicle control males were 20 and 20 g/animal/day, respectively. The mean initial (Week 0-1) and final (Week 5-6) food consumption of saline control females were 21 and 22 g/animal/day, respectively. The mean initial (Week 0-1) and final (Week 5-6) food consumption of vehicle control females were 21 and 22 g/animal/day, respectively. There were no significant treatment related effects on food consumption.

Ophthalmoscopy: Ophthalmoscopy was performed during acclimation (Week -1/-2) and Week 5. There were no significant treatment related ophthalmoscopic findings.

Electrocardiography (ECG): Not performed

Hematology: Hematology was conducted at Weeks 6 and 12. There were no significant treatment related hematology findings.

Clinical Chemistry: Clinical chemistry was conducted at Weeks 6 and 12.

In males, there were higher group mean values for serum ALP (20.5% higher than controls; mean 141 U/L vs. 117-118 U/L for controls) and serum ALT (36.4% higher than control; mean 60 U/L vs. 44-45 U/L for controls) values at 20 mg/kg compared to both controls. The higher ALT value was outside of the historical control


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range for the study means, but the ALP value was within the historical control range for the study means. There were no significant treatment related histopathological correlates. One animal (male no. 8270, 20 mg/kg) with an incidental partially infarcted liver lobe had the highest individual ALP value (195 U/L), and this isolated finding partly contributed to a higher group mean ALP. Relation to the treatment was unknown in the absence of dose response (as only one dose group was tested in this study), lack of histopathological correlates and values (ALP) were within the historical control range.

Urinalysis: Urinalysis was conducted at Weeks 6 and 12. There were no significant treatment related urinary findings.

Gross Pathology: Gross pathology was conducted at necropsy. There were no significant treatment related gross pathology findings at primary or recovery necropsies.

Organ Weights: The following (from page 40 of the report) organs were weighed from all animals at the scheduled necropsies.

There were no significant treatment related effects on organ weights at primary or recovery necropsies.

Histopathology: Microscopic examination was performed on all tissues as listed in the table below (from page 39 of the report) from all animals at the primary necropsy.


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Adequate Battery: Yes

Peer Review: There were no significant treatment related microscopic findings at the primary necropsy, thus the pathology peer review was not performed per protocol amendment 3.

Histological Findings: There were no significant test article related microscopic findings at the primary or recovery necropsies. Incidental findings or those findings attributed to experimental manipulations are discussed below.



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Lungs: In the lungs of all control and treated groups, there was subacute inflammation, edema, and hemorrhage, which were each considered to be a result of saline-based infusion. Saline or saline-based vehicle infusion has been associated with periarterial infiltrations of eosinophils and with medial hypertrophy of pulmonary vessels in the lungs of rats (Morton, D, et al., 1997, Histologic Lesions Associated with Intravenous Infusions of Large Volumes of Isotonic Saline Solution in Rats for 30 Days, Toxicol Pathol, 25(4): 390-394). There was no toxicologically relevant difference in severity or incidence of these findings between the saline control (Group 1), vehicle control (Group 2), or 20 mg/kg (Group 3) groups.

Infusion Site (femoral vein): There was vascular intimal thickening, intravascular thrombosis, medial hypertrophy, subacute inflammation of the vessel walls, and perivascular hemorrhage at the infusion site. The incidence and severity of these changes were similar between all groups, and were expected tissue reactions to placement of an infusion catheter. There was no significant test article related difference in the degree of such tissue reaction.

Infusion Site (Tail): In the animals with an infusion site in the tail, there was a low incidence and low severity of hemorrhage and subacute inflammation. These findings were within the expected range of tissue reaction to placement of a catheter.

Testes/Epididymides: In 4 male animals (nos. 8217 [saline control], 8290 [saline control], 8271 [vehicle control], and 8251 [20 mg/kg]), there was unilateral hypospermatogenesis in one of the testes and unilateral hypospermia in the epididymis. The seminiferous tubules were lined only by Sertoli cells, with nearly complete absence of spermatogenic epithelium. The epididymis was generally void of spermatozoa and occasionally contained cellular debris. In each of the affected animals, the contralateral testis and epididymis were normal. The cause for the unilateral cessation of spermatogenesis was unknown. However, this was also observed in the control animals. In the absence of a dose response and occurrences in control animals, these findings were not considered to be related to the test article.

Liver: One 20 mg/kg/dose group male (no. 8209) had mild periportal vacuolation of hepatocytes. This change was characterized by a mixture of micro and macrovesicles, and was not associated with alteration in the serum chemistry or the liver weight for that particular animal. The change was considered incidental and unrelated to test article. Another 20 mg/kg/dose group male (no. 8270) had a locally extensive chronic infarct of a liver lobe characterized by hemorrhage and fibrosis with little remaining hepatic parenchyma. The other liver parenchyma was normal. The infarct was considered a spurious finding likely secondary to torsion of the liver lobe. This was correlated in part to a high serum ALP level in this animal, which contributed to the high group mean serum ALP in the 20 mg/kg males. Torsion of a liver lobe was considered a sporadic finding in rats (Jones, T.C., 1967, Pathology of the Liver in Rats and Mice, In Pathology of Laboratory Rats and Mice, Cotchin, E.; Roe, F.J., Eds.; Oxford and Edinburgh, Blackwell Scientific Publications: Philadelphia, PA, p 16;



31

Thoolen, B, et al., 2010, Proliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System, Toxicol Pathol, 38 (7 Supplement), 5S-81S).

Special Evaluation: None

Toxicokinetics: Blood samples for toxicokinetics were collected from 3 animals/sex/time point from Group 2A animals at 1 and 4 hours after the start of infusion and from Group 3A animals at 30 minutes and 1, 2, 4, 8, and 24 hours after the start of infusion on study days 0 and 42.

Exposure (AUClast) in females was approximately 2-fold higher when compared to males on both days (Day 0 and 42). Cmax in males and females was similar on both days. For SCH 720881 (metabolite of rolapitant), AUClast in females was approximately 11 to 15-fold lower when compared to males on both days. Cmax for the metabolite in females was approximately 9-fold lower when compared to males on both days. Exposure to rolapitant and SCH 720881 was similar on both days. Exposure to SCH 720881 was lower when compared to rolapitant. Metabolite to parent ratios ranged from 0.00593 (0.593%) to 0.0068 (0.680%) in females and 0.157 (15.7%) to 0.183 (18.3%) in males. Exposure data and differences in metabolite to parent ratios indicated that male rats metabolized rolapitant to SCH 720881 at a higher level when compared to females. For rolapitant, terminal half-life (t1/2) ranged from 7.14 to 8.01 hours in males and from 25.1 to 29.3 hours in females. For SCH 720881, t1/2 ranged from 19.0 to 22.5 hours in males and the half-life was not calculable in females. The following (from page 51 of the report) table shows the TK parameters.

Dosing Solution Analysis: Dosing solution analysis report was not included in the study report.



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Study title: 13-Week Intravenous Infusion Toxicity Study in Rats with a 6-Week Recovery Period

Study no.: 15-3889Study report location: EDR SDN 001, Section 4.2.3.2

Conducting laboratory and location: Date of study initiation: Not provided


Drug, lot #, and % purity: Rolapitant HCl monohydrate. Lot # and purity data were not provided.

This study was originally designed to examine the toxicity and toxicokinetics of rolapitant when administered daily to rats, via a 30-minute intravenous (IV) infusion, for 13 weeks and to evaluate recovery during a 6-week treatment-free recovery period. The original study design is shown below (from page 8 of the report).

Due to numerous unscheduled deaths (from Day 14 through 27) throughout the saline control, placebo control and test article treated groups; this study was terminated early, with treatment duration of ~26 to 29 days. Many of the unscheduled decedents had large masses and/or thickened areas/swelling externally and internally at the location of the catheter vein, tip or insertion site. Necropsy findings included abnormal material and thickening of the skin, catheter tip, and catheter vein, causing inflammation and abscess. Additionally, in many animals, the catheter was not present in the anticipated location in the vena cava, or was outside of the vena cava. Preliminary results indicated that the observations may be associated with the misplacement of the catheters. The Applicant stated “In our professional experience and judgment, the study was not going to achieve the original goal of three-month dose duration with interpretable results. The study was therefore discontinued to investigate and address potential formulation and/or catheter-related issues.” The Sponsor did not provide the details of the methods and results of this study.


(b) (4)


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Study title: 13-Week Intravenous Infusion Toxicity Study in Rats Study no.: 15-3893

Study report location: EDR SDN 001, Section 4.2.3.2Conducting laboratory and location:

Date of study initiation: May 22, 2015GLP compliance: Yes

QA statement: YesDrug, lot #, and % purity: Rolapitant HCl monohydrate, Lot No.

22901.001, 100.3%

Key Study Findings: There were mortalities in all groups including the saline and vehicle (placebo)

treated animals (number of unscheduled sacrifices or deaths/total number in group = 3/26, 13/36, 12/32, 9/32, and 15/42 for saline, placebo, and 10, 20, and 40 mg/kg/day, respectively).

Treatment related clinical signs included convulsions at 40 mg/kg/day. Infusion site reactions included abscess formation, bacteremia and/or

inflammation, which were observed across all groups including the saline and placebo control. However, the incidence and severity was higher in the placebo control and rolapitant groups when compared to the saline control group.

Test article related clinical pathology changes included minimal to marked increases in AST and ALT at ≥20 mg/kg/day in unscheduled decedents. AST and ALT increases were considered to be test article related due to the greater magnitude and increased incidences observed in Group 4 animals.

Placebo-related clinical chemistry changes in unscheduled decedents included increased ALP, AST, ALT, bilirubin, urea nitrogen, and creatinine and increased ALP in animals surviving to termination.

Placebo-related hematology changes included decreases in red cell mass with or without increases in reticulocytes and Red Cell Distribution Width (RDW), and increases in total White Blood Cell (WBC), neutrophils, monocytes, and/or lymphocytes.

Increases in liver weights were observed in males at 20 mg/kg/day and in both sexes at 40 mg/kg/day.

There were no significant test article related macroscopic or microscopic findings. Placebo related histopathological changes were observed in the liver (pigment deposition within macrophages and granulomatous inflammation).

The NOAEL could not be determined as treatment related changes were observed at all doses.


(b) (4)


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Methods: Doses: 0 (saline), 0 (vehicle), 10, 20, and 40 mg/kg/day

Frequency of dosing: Once daily Route of administration: Intravenous (IV) infusion (30-minute)

Dose volume: 5 mL/kgFormulation/Vehicle: 4.4% Solutol® HS15, 1.1% mid-chain

triglycerides (MCT), and 0.66% soybean oil in 20 mM phosphate-buffered saline (PBS) pH 7.5.

Species/Strain: Sprague Dawley (SD) ratsNumber/Sex/Group: 10/sex/group

Age: Animals were approximately 77 days old at the initiation of the treatment

Weight: Males: 228 to 375 g; Females: 204 to 289 gSatellite groups: Toxicokinetic (TK)

Unique study design: Shown in the table below Deviation from study protocol: Protocol deviations were not considered to have

compromised the validity or integrity of the study.


Basis of Dose Selection: The dose selection was based on the results of a 14-day IV toxicity study (SN 07395, pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD) and 14-day IV Dose Range-Finding (DRF) study (Study No. 14-3875) in rats. In addition, a 7-day IV DRF study (Study No. 14-3882, non-GLP) at 30, 40, 50, and 60 mg/kg/day was also conducted to help the dose selection for the current study.

In the 7-day IV (30-minute infusion) DRF study in rats, animals (n = 6/sex/dose) were treated with rolapitant HCl monohydrate at 0 [4.4% polyoxyl 15 hydroxystearate (Solutol HS 15, 1.1% MCT and 0.66% soybean oil in PBS buffer, pH 7.5), 30, 40, 50, and 60



35

mg/kg/day. Clinical signs observed at Day 1 at 60 mg/kg/day in both sexes included convulsions, splayed limbs, tremors and prostration. On Day 2, the 60 mg/kg/day dose group was terminated and the animals were euthanized for humane reasons. In addition, there were adverse clinical signs observed at 50 mg/kg/day in both sexes on Day 1, which persisted through the end of treatment. These clinical signs at 50 mg/kg/day included splayed limbs, decreased activity, increased sensitivity, abnormally cold to touch, tremors, pale, piloerection, hunched, and irregular/rapid/slow breathing. No significant clinical signs were observed at 30 or 40 mg/kg/day. Treatment related clinical pathology findings in decedent rats included increases in WBC, including neutrophils and monocytes, and increases in AST and chloride, and decreases in glucose. Macroscopic evaluations in 1 of 6 males at 60 mg/kg/day included red, firm mass on the accessory lobe of the liver and pale, green areas on the left lobe of the liver in 1 of 6 females at 60 mg/kg/day.

In the 14-day IV (30-minute infusion) study (Study No. 14-3875) in rats, the intended doses were 0 (saline), 0 [vehicle: 4.4% polyoxyl 15 hydroxystearate (Solutol HS 15), 1.1% MCT and 0.66% refined soybean oil in PBS, pH 7.5 ), 10, 20, and 40 mg/kg/day. However, during the initial week of treatment, it was noted that only half of the intended dose level was being administered (5, 10, and 20 mg/kg/day). As the initial dose levels and volumes were incorrect (half the intended dose), the study was discontinued after either 6 days (TK), 7 days (tox: females), or 8 days (tox: males) of treatment, and a drug wash-out period of 7-9 days was performed, in order to restart the study with the correct dose levels and dose volumes for all groups. The study was restarted at 10, 20 and 40 mg/kg/day. The following table (from page 8 of the report shows the study design).

It is to be noted here that this study was originally designed for 13 weeks of treatment with a 6-week recovery period. However, subsequent to the restart of the study, the decision was made to terminate treatment after 14 days at the new dose levels rather than continue with 13 weeks followed by a recovery, providing more information for



36

dose selection/refinement for the 3-month pivotal rat toxicity study. The Applicant decided that the study would be difficult to interpret due to the acclimation to the test article at a lower dose level, and the overall integrity of the study could be questioned. The sponsor did not provide details of the methods and results of this study. Treatment related clinical signs during Week 1 in both sexes at 40 mg/kg/day included convulsion, decreased activity, partially-closed and/or prominent eyes, flattened posture, irregular breathing, and excessive chewing. These findings generally resolved at Week 2, with decreased activity, the most consistent finding at Week 2. Additionally at 40 mg/kg/day, in Week 1, there was decreased body weight gain in both sexes. Treatment related decreases in body weight gain were observed in females at 5 and 40 mg/kg/day (-10% of mean saline control on Day 14). There were decreases in food consumption in both sexes in the second treatment phase at 5 and 40 mg/kg/day (-27 and -29%, respectively of mean saline control values in Week 1), however, food consumption increased in these animals to -10 and -20% of mean saline control values by the end of 14 days of treatment. Macroscopic evaluations were performed on the two unscheduled decedents at 5 and 40 mg/kg/day [Animal Nos. 7035 (toxicity male) and No. 7562 (TK female)] and macroscopic findings in these animals included masses at the catheter insertion site and scrotum, and edema and thickening in the catheter vein and insertion site, respectively. There was no scheduled histopathology.

Based on the results of the above studies, the high dose for the current study was selected as 40 mg/kg/day. Mid dose (20 mg/kg/day) was half of the high dose, and low dose (10 mg/kg/day) was half of the mid-dose.


Mortality: All animals were observed twice daily for mortality.

There were a total of 52 unscheduled decedents. Primary cause of morbidity or mortality was bacterial infection, marked to severe abscesses and/or inflammation of the catheterized vein with or without systemic spread to other organs such as liver and/or kidneys. In addition, five animals were euthanized due to convulsions. Three of those 5 animals were in the 40 mg/kg/day dose group, and 2 of 3 animals were sacrificed for humane reasons on Day 2 and 4. One animal at 10 mg/kg/day also had convulsions on Day 61 and was found to have an abscess at necropsy. On Day 40, one placebo animal also had convulsion. At necropsy, adrenal glands, mediastinal lymph node, and spleen were found to be enlarged in this placebo treated animal. The following table (from page 53 of the report) shows the mortalities.



37

Clinical Signs: Clinical signs were observed twice daily.

Convulsions were observed at 0 (placebo/vehicle), 10, and 40 mg/kg/day in animal nos. 5561, 5563, 2548, 5059, and 3040 (Days of deaths/sacrifice: 2, 4, 40, 52, and 61, respectively). Other clinical observations in the early decedents in placebo (vehicle) and rolapitant treated males and females generally included distended abdomen/swollen areas, impaired locomotion/irregular gait, dark abdominal/inguinal areas, masses/firm areas, vocalization upon touch, decreased activity, thinness, hunched or flattened posture, ulcerated skin, and/or labored/irregular/rapid breathing, indicative of poor clinical condition.


Mean initial (Week 1) and final (Week 13) body weights of saline control (Group 1) males were 351 and 537 g, respectively. The mean initial (Week 1) and final (Week 13) body weights of placebo vehicle control (Group 2) males were 354 and 548 g, respectively. The mean initial (Week 1) and final (Week 13) body weights of saline control (Group 1) females were 239 and 296 g, respectively. The mean initial (Week 1) and final (Week 13) body weights of vehicle control females (Group 2) were 249 and 299 g, respectively. There were no significant treatment related effects on body weights.

Feed Consumption: Food consumptions were recorded on a weekly basis.

Mean initial (Week 1) and final (Week 13) food consumptions of saline control (Group 1) males were 25 and 27 g/animal/day, respectively. Mean initial (Week 1) and final (Week 13) food consumptions of placebo vehicle control (Group 2) males were 24 and 27 g/animal/day, respectively. Mean initial (Week 1) and final (Week 13) food consumptions of saline control (Group 1) females were 18 and 20 g/animal/day, respectively. Mean initial (Week 1) and final (Week 13) food consumptions of vehicle



38

control (Group 2) females were 19 and 19 g/animal/day, respectively. There were no significant treatment related effects on food consumption.

Ophthalmoscopy: Ophthalmoscopy was performed at the pretest and at the end of the dosing. There were no significant treatment related ophthalmoscopy findings.

Electrocardiography (ECG): Not performed

Hematology: Hematology was conducted at end of dosing.

Unscheduled Decedents: Treatment related hematology changes in unscheduled decedents included decreases in RBC mass (hemoglobin, hematocrit and RBC) with or without increases in reticulocytes and Red cell Distribution Width (RDW), and increases in total WBC, neutrophils, monocytes, and/or lymphocytes. Changes were observed in Groups 2-5 with no consistent dose related trends, and were considered to be related to placebo. The following table (from page 56 of the report) shows the hematology changes.

Scheduled Sacrifice: There were no significant treatment related hematology changes in animals surviving to their scheduled termination.

Clinical Chemistry: Clinical chemistry was conducted at the end of dosing.

Unscheduled Decedents: Most notable change included a slight to moderate increase in ALP in both sexes administered placebo (Group 2) and at ≥10 mg/kg (Groups 3 to 5). In addition, there were minimal to marked increases in AST and ALT in Group 2 and 5 males and Group 4 and 5 females, minimal increases in bilirubin (Group 2 males and Group 4 females), urea nitrogen (Group 2 and 4 females) and creatinine



39

(Group 2 females). Most changes were considered vehicle related, with the exception of increases in AST and ALT, which were considered to be related to the test article. The following table (from page 57 of the report) shows the clinical chemistry changes in decedent animals.

Scheduled Sacrifice: Clinical chemistry changes were limited to increases in ALP in males and females in Groups 2, 3, 4 and 5. These ALP increases were considered to be vehicle related.

Urinalysis: Urine was collected overnight (approximately 16 hours) from animals housed in metabolism cages. Time of collection was not mentioned. There were no significant treatment related urinary changes.

Gross Pathology: Gross pathology was conducted at necropsy. There were no significant treatment related gross pathology findings.

Organ Weights: The following (from page 32-34 of the report) organs were weighed from all animals at the scheduled necropsies.



40



41



42

Dose-related increase in liver weights in males at 20 mg/kg/day and in males and females at 40 mg/kg/day were observed, however, there were no histopathological correlates. The following table (from page 59 of the report) shows the liver weight changes.

Kidney, prostate/seminal vesicle and adrenal gland weights were increased when compared to the saline control group (Group 1). These differences were considered secondary to abscesses and inflammation at the infusion sites. Higher mean kidney weights were associated with abscess/inflammation in 1 of 8 males at 20 mg/kg/day, and 3 of 11 males and 1 of 9 females at 40 mg/kg/day. Lower mean weights for prostate/seminal vesicles in 40 mg/kg/day group males and increased mean weights for adrenal glands in 40 mg/kg/day group females were also associated with abscesses and inflammation. Decreased pituitary gland weight in rolapitant treated females lacked a histologic correlate and was not considered rolapitant related.

Histopathology: Microscopic examination was performed on all tissues as listed in the above table from all animals at the primary necropsy.


Peer Review: Yes

Histological Findings: Histopathological changes were observed in the liver (pigment in macrophages, granulomatous inflammation) when compared to saline



43

control. Granulomatous inflammation consisted of generalized Kupffer cell hypertrophy and hyperplasia and randomly scattered granulomas composed of macrophages, with lesser numbers of lymphocytes, plasma cells, and/or occasional necrotic hepatocytes. These finds were considered vehicle (placebo) related findings as these were also observed in placebo treated rats except for granulomatous inflammation in males. The following table (from page 60 of the report) shows the liver findings.

In addition, procedure and placebo related histopathological changes were observed at the infusion sites (abscess formation with or without bacterial infection and inflammation). The incidence and severity of the changes were greater in the placebo-treated groups with no consistent relationship to rolapitant. The following table (from page 61 of the report) shows the infusion site changes.

Secondary Findings: Findings considered secondary to infusion site abscess formation and/or inflammation were observed in the lungs, kidneys, spleen, adrenal glands, thymus, and bone marrow in saline control, placebo vehicle, and rolapitant treated groups. Lung findings included pulmonary arterial thromboembolism, perivascular and interstitial inflammation, bronchial/bronchiolar mucus cell hyperplasia, aggregates of alveolar macrophages, alveolar hemorrhage, and the presence of perivascular foreign body granulomas. Similar findings have been reported in infusion studies in rats (Morton, D. et al., 1997, Histologic Lesions Associated with Intravenous Infusions of Large Volumes of Isotonic Saline Solution in Rats for 30 Days, Journal of Toxicol Pathol, 25: 390-394). Kidney findings included pyelonephritis, an infectious inflammatory condition that was present in both sexes in all groups except saline controls.



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Toxicokinetics: On Days 1 and 30, blood samples were obtained for TK analyses from 3 animals/sex/time point from Groups 1 and 2 at 1 and 4 hours postdose and from Groups 3-5 at 30 minutes, 1, 2, 4, 8 and 24 hours postdose.

Rolapitant: On Day 1, Cmax values of rolapitant increased more than dose proportionately over the dose range 10 to 40 mg/kg/day. However, on Day 30, Cmax values increased less than the dose proportionately. Systemic exposure (AUC0-24h) to rolapitant increased approximately proportionately with increasing dose over the dose range 10 to 40 mg/kg/day on Day 1, but slightly less than the proportionately on Day 30. Cmax values of rolapitant in female rats were similar to those in males on Day 1; however, AUC0-24h values were 1.1 to 1.6-fold higher than those in males. On Day 30, both Cmax and AUC0-24h values in females were similar to those in males. After repeated doses (Day 30), Cmax and AUC0-24h values for rolapitant were generally similar to those values after a single dose (Day 1) at 10 and 20 mg/kg/day; however, at 40 mg/kg/day, these values were lower. The accumulation ratios, based on AUC0-24h values, were generally close to 1 at 10 and 20 mg/kg/day. In general, the results indicated little or no accumulation of rolapitant following repeated dosing. Toxicokinetic parameters for rolapitant are shown in the following (from page 51 of the report) table.

SCH720881 (Metabolite): On Day 1, Cmax values for SCH720881 increased approximately proportionately with increasing dose over the dose range 10 to 40 mg/kg/day; however, on Day 30, Cmax values increased by less than the proportionately. AUC0-24h values for SCH720881 increased approximately dose proportionately over the dose range 10 to 40 mg/kg/day on Day 1, however, on Day 30, the AUC0-24h values increased less than the dose proportionately. Cmax and AUC0-24h values for SCH720881 were about 88% lower on Day 1 and about 69% lower on Day 30 than those in males. After repeated doses (Day 30), Cmax and AUC0-24h values for SCH720881 were generally similar to those values after a single dose (Day 1) in males, however, they were higher than the values after a single dose in females. In males, the accumulation



45

ratios, based on AUC0-24h values, were lower than 1 indicating little or no accumulation of SCH720881 after repeated dosing of rolapitant. In females, however, the accumulation ratios were greater than 1 indicating accumulation of SCH720881 following repeated dosing. The following table (from page 52 of the report) shows the TK parameters for SCH 720881.


Study title: 28-Day Intravenous Infusion Toxicity Study in Cynomolgus Monkeys with a 28-Day Recovery Period

Study no.: 2013-012Study report location: EDR, Section 4.2.3.2

Conducting laboratory and location: Date of study initiation: January 3, 2014


Drug, lot #, and % purity: Rolapitant solution, Lot no. 13 0314-047 (101.3%), 13 0314-078 (99.7%)

Key Study Findings: There were no mortalities or significant treatment related clinical signs. There were no significant treatment related effects on body weights, organ

weight, and clinical pathology parameters. There was no significant treatment related gross or histopathology findings.

Some of the histopathology findings (decreased diffuse vacuolation of the adrenal gland cortex and brown pigmentation) appeared to be related to the vehicle.


(b) (4)

(b) (4)

(b) (4)


46

The NOAEL was considered as 15 mg/kg/day.

Methods:

Doses: 0 (saline), 0 (vehicle), 3, 10 and 15 mg/kg/dayFrequency of dosing: Once daily

Route of administration: Intravenous (IV) infusion (30-minute)Dose volume: 7.5 mL/kg

Formulation/Vehicle: 4.4% Solutol® HS15, 1.1% Medium-Chain Triglycerides (MCT), and 0.66% soybean oil in 20 mM Phosphate-Buffered Saline (PBS), pH 7.5

Species/Strain: Cynomolgus monkeysNumber/Sex/Group: 4-6/sex/group

Age: 2 year and 4 months to 3 years and 10 months Weight: Male: 2.55 to 3.32 kg; Female: 2.43 to 3.41 kg

Satellite groups: Toxicokinetic (TK)Unique study design: Shown in the table below

Deviation from study protocol: Protocol deviations did not affect the quality or integrity of the study.


Basis of Dose Selection: The dose levels were selected based on the results of a 14-day IV infusion study in cynomolgus monkeys (Study Number 2013-009, please refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing). In this study, rolapitant was administered once daily by IV infusion at 3 and 10 mg/kg/day for 30 minutes, and at 15 and 20 mg/kg/day for 45 minutes, respectively. There was no mortality. Dose was reduced from 20 mg/kg/day to 15 mg/kg/day due to adverse clinical signs (decreased activity, convulsions, lateral recumbency, partially and/or completely



47

closed eyelids, and shallow breathing, dilated pupils, salivation, and ataxia immediately after treatment). There were no significant treatment related histopathology findings. Based on this, the high dose of 15 mg/kg/day was selected for the current study, the low dose of 3 mg/kg/day was expected to have no adverse effects, and the mid dose of 10 mg/kg/day was selected to demonstrate dose-response.


Mortality: Animals were observed twice daily for mortality and moribundity. There were no mortalities.

Clinical Signs: Clinical signs were observed prior to infusion and at approximately 45 minutes and 4 hours postdose. There were no significant treatment related or vehicle related clinical signs.


Mean initial (Week 0) and final (Day 26) body weights of saline control males were 2.9 and 3.0 kg, respectively. Mean initial (Week 0) and final (Day 26) body weights of vehicle control males were 2.8 and 2.9 kg, respectively. Mean initial (Week 0) and final (Day 26) body weights of saline control females were 2.8 and 2.7 kg, respectively. Mean initial (Week 0) and final (Day 26) body weights of vehicle control females were 2.9 and 2.9 kg, respectively. There were no significant treatment related effects on body weights.

Feed Consumption: Food consumptions were recorded qualitatively on a daily basis. Quantitative food consumption data were not provided.

Ophthalmoscopy: Ophthalmoscopy was performed at pretest and prior to scheduled necropsy. There were no significant treatment related ophthalmoscopic findings.

Electrocardiography (ECG): ECG was performed at pretest, predose and 30 minutes postdose on Days 1 and 28, and prior to the recovery necropsy. Sinus tachycardia (an average heart rate > 270 beats/min) was observed in 4 animals in the vehicle control group. All instances of sinus tachycardia occurred in the vehicle control group (1 instance) or at pretest (3 instances) or recovery (1 instance) intervals. There were no significant rolapitant related ECG findings.

Hematology: Hematology was conducted at pretest and prior to the terminal and recovery necropsy. At the terminal collection, mild reductions in red cell mass (erythrocytes, hemoglobin and hematocrit; up to -19%) and minimal to mild increases in absolute reticulocytes (up to +139%) were observed in all groups (including saline and vehicle controls), relative to pretest values in both sexes. These effects were considered secondary to procedure related blood loss (blood collections, etc.), and were considered unrelated to the test article or vehicle. Overall, there were no significant meaningful treatment related effects on hematology parameters.



48

Clinical Chemistry: Clinical chemistry was conducted at pretest and prior to the terminal and recovery necropsy.

Mild to moderate decreases in cholesterol was observed in both sexes in the vehicle control (up to -50%), and at 3 (up to -26%), 10 (up to -45%) and 15 mg/kg/day (up to -44%), relative to pretest values. Reductions in cholesterol were considered vehicle related, and were fully recovered by the end of the recovery period in both sexes receiving the vehicle alone and at 15 mg/kg/day. Based on their low magnitude and lack of dose response and full recovery, reductions in cholesterol were not considered adverse.

With the exception of females at 15 mg/kg/day, elevations in AST and ALT were approximately +3-fold and +2-fold, respectively, relative to pretest values. The magnitude of the increase in AST in females at 15 mg/kg/day (+6.1-fold vs pretest value) was largely attributed to one female (animal no. 5501), where AST was increased by 23.4-fold, relative to the individual pretest value, and approximately 8-fold, relative to the mean saline control. With the exception of animal number 5501, increases in AST and ALT were of generally similar magnitudes across all groups. The increase in AST in animal number 5501 was not considered test article related due to the sporadic nature of the change and lack of histopathological correlate. Overall, there were no significant meaningful test article related effects on clinical chemistry parameters.

Urinalysis: Urine samples were collected for at least 16 hours (time of collection was not mentioned). There were no significant treatment related urinary effects.

Gross Pathology: Gross pathology was conducted at necropsy. Brown adrenal glands were observed in two terminal males at 15 mg/kg/day, one terminal female vehicle control, and one terminal female at 10 mg/kg/day. Microscopic correlate was decreased diffuse cortical vacuolation. Brown adrenal glands were considered related to the vehicle and not test article related, as this was seen in the vehicle control group. There were no other significant test article related gross pathology findings at primary or recovery necropsies.

Organ Weights: The following (from page 865 of the report) organs were weighed from all animals at the scheduled necropsies.



49


Histopathology: Microscopic examination was performed on all tissues as listed in the above table from all animals at the primary and recovery necropsy.


Peer Review: Yes

Histological Findings: Decreased diffuse vacuolation of the adrenal cortex was observed in the vehicle control, 3 (male only), 10, and 15 mg/kg/day terminal male and female monkeys. The cytoplasm of cortical cells in the zona fasicularis stained more eosinophilic and lacked the normal microvesicular appearance. This change correlated



53

Female:

Tissue Findings Severity Saline Vehicle 3 mg/kg/d

10 mg/kg/d

15 mg/kg/d

N 4 4 4 4 4LiverPigment, increased Kupffer cell

Minimal 0 2 0 0 3


Toxicokinetics: Blood samples were collected from all animals at predose, within 2 minutes prior to the end of infusion (30 or 45 minutes following the start of infusion), 1, 3, 6, 8, and 24 hours postdose on Days 1 and 28.

There were no apparent sex difference in mean systemic exposure to rolapitant and SCH 720881 (metabolite). Mean systemic exposure (AUC0-24hr) to rolapitant and SCH 720881 increased with increasing dose in an approximately dose proportional manner across the dose range. Following repeated administration, mean systemic exposure (AUC0-24hr) to rolapitant did not appear to change. Following repeated administration, mean systemic exposure (AUC0-24hr) to SCH 720881 appeared greater than that on Day 1. Systemic exposure (AUC0-24hr) to SCH 720881 was lower than systemic exposure to rolapitant. The Metabolite:Parent (M/P) ratios did not appear to change with increasing dose, and appeared to increase following repeated administration. Mean TK parameters are shown in the following table (from page 760 of the report).



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Study title: 13-Week Intravenous Infusion Toxicity Study in Cynomolgus Monkeys with a 6-Week Recovery Period

Study no.: 2013-015Study report location: EDR, Section 4.2.3.2

Conducting laboratory and location: Date of study initiation: November 17, 2014


Drug, lot #, and % purity: Rolapitant IV 2 mg/mL, Lot No. 22901.001, 99.9-100.7%

Key Study Findings: There was no mortality. Treatment related clinical signs at 15 mg/kg/day included convulsions, tremor

and decreased activity. There were no significant test article related effects on body weight, ophthalmic

evaluations, and there were no significant meaningful differences were observed in clinical pathology parameters.

There was no significant test article related macroscopic or microscopic changes. Histopathological changes were considered to be due to the vehicle and were not

considered adverse as they recovered at the end of the 6-week recovery period. The NOAEL was considered as 10 mg/kg/day.


(b) (4)


55

Methods: Doses: 0 (saline), 0 (vehicle), 3, 10 and 15 mg/kg/day

Frequency of dosing: Once daily Route of administration: Intravenous (IV) infusion (30-minute)

Dose volume: 1.5-7.5 mL/kgFormulation/Vehicle: 4.4% Solutol® HS15, 1.1% mid-chain

triglycerides (MCT), and 0.66% soybean oil in 20 mM phosphate-buffered saline (PBS) pH 7.5.

Species/Strain: Cynomolgus monkeysNumber/Sex/Group: 4-6/sex/group

Age: 3 years to 5 years 10 months of age Weight: Male: 3.20 to 6.25 kg; Female: 3.05 to 4.80 kg

Satellite groups: NoneUnique study design: Shown in the table below

Deviation from study protocol: Protocol deviations did not affect the quality or integrity of the study.

The study design is shown below (from page 10 and 49 of the report).



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Beginning on Day 11, one female at 15 mg/kg/day (animal number 5502) had the infusion duration extended to 90 minutes and beginning on Day 55, the dose level for this animal was reduced to 12.5 mg/kg/day at a rate of 6.25 mL/kg. This animal was a Group 5 animal but was reported separately on tables at a dose level of 15/12.5 mg/kg/day. Beginning on January 11, 2015, the infusion duration for all remaining males and females at 15 mg/kg/day was extended to 45 minutes.

Basis of Dose Selection: The dose levels were selected based on the results of a 14-day IV infusion study (Study Number 2013-009, refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD) and the 28-day study (Study Number 2013-012, reviewed above) in cynomolgus monkeys.

In the 14-day study (Study Number 2013-009), rolapitant was administered once daily by IV infusion at 3 and 10 mg/kg/day for 30 minutes, and at 15 and 20 mg/kg/day for 45 minutes, respectively. There was no mortality. Dose was reduced from 20 mg/kg/day to 15 mg/kg/day due to adverse clinical signs (decreased activity, convulsions, lateral recumbency, partially and/or completely closed eyelids, and shallow breathing, dilated pupils, salivation, and ataxia immediately postdose). There were no significant treatment related histopathology findings. Based on this, a high dose of 15 mg/kg/day was selected for the current study, the low dose of 3 mg/kg/day was expected to have no adverse effects, and the mid dose of 10 mg/kg/day was selected to demonstrate dose-response.


Mortality: All animals were observed twice daily for mortality and moribundity. There were no mortalities.

Clinical Signs: Clinical signs were observed prior to infusion and at approximately 45 minutes and 4 hours postdose. Treatment related clinical signs at 15 mg/kg/day included convulsions, tremors, and decreased activity.

Convulsion/Tremor: At 15 mg/kg/day on Day 4, two high dose male animals (# 5001 and 5002) had convulsions at 45 minute postdose, which were resolved by 4 hour postdose. Tremors were observed for animal # 5003 (high dose male) on Days 21-23; animal # 5503 (high dose female) on Days 8, 19, and 44; animal # 5505 (high dose female) on Day 2; animal # 5502 (high dose female) on Days 15, 20-22, 25-27, 32, 33, 48, 49, 52; and animal # 5506 (high dose female) on Day 8. These observations were considered test article related.

Decreased Activity: Animal # 4503 (female, 10 mg/kg) exhibited decreased activity on Days 78 and 79; animal # 5502 (female, 15 mg/kg) on Days 23, 25, 35, and 39; and animal # 5504 (female, 15 mg/kg) on Days 25, 26, 27, and 28 and control animal # 1002 (male) on Day 51 and placebo animal # 2503 (female) on Day 34. Even though a control animal showed this sign, the frequency and number of animal affected in the treated groups showed a test article related trend.



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-42%) and 15 mg/kg/day (up to -41%) of rolapitant, and in the female at 12.5/15 mg/kg/day (-24%), relative to pretest values. Reductions in cholesterol concentration were considered vehicle-related, and fully resolved by the end of the recovery period. Based on their low magnitude and recovery, reductions in cholesterol were not considered adverse. Minimal to mild decreases in albumin concentration (up to -11%) with concomitant minimal to mild increases in globulin concentration (up to +15%) were observed in both sexes administered the vehicle and at 10 and 15 mg/kg/day of rolapitant, relative to pretest values. These were considered likely vehicle related and were recovered by the end of the recovery period. There were no other significant meaningful treatment related effects on clinical chemistry parameters.

Urinalysis: Urine samples were collected for at least 16 hours (time of collection was not mentioned). There were no significant treatment related urinary changes.

Gross Pathology: Gross pathology was conducted at necropsy. There were no significant treatment related gross macroscopic changes.

Organ Weights: The following (from page 1116 of the report) organs were weighed from all animals from all dose groups at the scheduled necropsies.



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Histopathology: Microscopic examination was performed on all tissues as listed in the table above from all animals from all groups at the primary and recovery necropsy (Group 2 and 5).


Peer Review: Yes

Histological Findings: Microscopic changes associated with the terminal placebo control and rolapitant groups included decreased vacuolation of the adrenal gland cortex,



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pigment within liver Kupffer cells, mandibular and/or mesenteric lymph node macrophages, spleen macrophages, and bone marrow macrophages (females only), and hepatocellular hypertrophy (males only). These changes were considered to be vehicle-related, and were not considered adverse as they recovered at the end of the 6-week recovery period and lack of cellular degeneration/necrosis in any organs listed in the above table. Histopathological changes are shown in the following table (from page 28 of the report).



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Microscopic changes observed in the recovery placebo control and rolapitant treated groups (decreased vacuolation of the adrenal gland cortex, pigment within liver Kupffer cells, mandibular and/or mesenteric lymph node macrophages, spleen macrophages, and bone marrow macrophages) showed almost complete reversibility after a 6-week recovery period. Hepatocellular hypertrophy of the liver was not present and was considered to be completely reversible after a 6-week recovery period. These changes



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were considered to be related to the vehicle as these changes were seen in the vehicle control animals. Histopathological findings in the recovery animals are shown in the following table (from page 29 of the report).

Overall, there were no significant test article related microscopic changes in terminal or recovery animals.




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8 CarcinogenicityPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

9 Reproductive and Developmental Toxicology9.1 Fertility and Early Embryonic DevelopmentPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

9.2 Embryonic Fetal DevelopmentPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

9.3 Prenatal and Postnatal DevelopmentPlease refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD.

10 Special Toxicology StudiesN/A

11 Integrated Summary and Safety EvaluationThe Applicant has conducted 13-week intravenous (infusion) toxicity studies in rats and 28-day and 13-week intravenous (infusion) toxicity studies in cynomolgus monkeys to support the intravenous rolapitant formulation. The Central Nervous System (CNS) appeared to be the primary target organ. Treatment related convulsions and tremors were observed in these studies. Vehicle related effects (clinical pathology and histopathology changes in the liver) were also observed in these studies. In addition, infusion site reactions were observed, which included abscess formation and/or inflammation. The NOAEL could not be determined for the 13-week rat study due to mortality observed at all placebo and rolapitant dose levels. The NOAEL in the 13-week study in cynomolgus monkeys was 10 mg/kg/day. Some of the histopathological findings (diffuse vacuolation of the adrenal cortex and brown pigmentation of adrenal glands and Kupffer cells in the liver) in monkey studies appeared to be related to the vehicle. Please refer to pharmacology review of NDA 206500 dated March 19, 2015 by Tracy L. Behrsing, PhD for other nonclinical studies with rolapitant including reproductive toxicity, genotoxicity, and carcinogenicity.

The recommended dosage of Varubi (rolapitant) injectable emulsion for intravenous use is 166.5 mg (~3 mg/kg or 0.214 mg/kg/day) of rolapitant administered every 14 days. The NOAEL of 10 mg/kg/day identified in the 13-week intravenous toxicity study in cynomolgus monkeys offer adequate (approximately 15-fold based on body surface



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area) margin of safety for the proposed dose of 166.5 mg of rolapitant administered every 14 days or 0.214 mg/kg/day. The following table (from page 20 of Section 2.4 of the submission) shows the exposure multiples for rolapitant and its metabolite at the NOAEL in animals and humans. Overall, from a nonclinical standpoint, there are no approvability issues.

12 Appendix/AttachmentsNone


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TAMAL K CHAKRABORTI11/28/2016

SUSHANTA K CHAKDER11/28/2016


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